Use of ascorbic acid to reduce irritation of topically applied active ingredients

ABSTRACT

The use of an effective amount of ascorbic acid (Vitamin C) or one or more of its derivatives, has been found to decrease skin irritation caused by the topical administration of an active ingredient for treating a skin condition. Examples of the active ingredient include α-hydroxy acids, β-hydroxy acids, keto acids, benzoyl peroxide, retinol (Vitamin A) , retinoic acid, retinal, Vitamin A 2 , Vitamin A epoxide, lactamides and quaternary ammonium lactates, C 4-12  hydroxylated carboxylic acids, sulfur, resorcinol and salicylic acid, and various derivatives thereof. The ascorbic acid (or its derivatives) is present in effective amounts from about 0.5% to about 25% by weight. It is provided by topical application of a separate solution or by admixture with a cosmetically or pharmaceutically acceptable vehicle for the active ingredient.

This application is a continuation of Ser. No. 08/053,989 filed on Apr.26, 1993, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to dermatologic agents which reduce irritationcaused by the topical application of an active ingredient used to treata skin condition. More particularly, ascorbic acid or a derivativeproduct is added to a cosmetically and/or pharmaceutically acceptablevehicle to reduce the irritation reaction.

2. State of the Art

Human skin is a complex organ which extends over the entire body. Thereare different types of skin at different locations on the body. Forexample, facial skin differs from skin on the scalp; and skin on thefront (palm) of the hand is different from that on the back. Althoughthe type of skin can vary over a person's body, skin is generallycomposed of two main layers of tissue. The outermost layer is theepidermis or cuticle. It is composed of three superficial and two deeplayers. The derma, corium, or cutis vera, the true skin, is composed ofa papillary layer above and a reticular layer below.

Since ancient times, a variety of substances have been used to improveskin appearance. Early techniques were generally directed to theoutermost layer of skin, or to ailments found on the true skin. Morerecently, efforts have been made to rejuvenate the skin and reclaimelasticity or suppleness lost from aging and/or exposure to sunlight (UVradiation) and weather.

U.S. Pat. No. 3,897,537 describes several α-hydroxy acids, keto acidsand esters thereof which are useful in the treatment of ichthyosiformdermatoses. These conditions are characterized by a fish-scaleappearance typically caused by hereditary disorders. This patentcontemplates daily application of a composition with at least one lowerorganic hydroxy acid, keto acid or esters thereof in the range from 1 to20 weight percent.

Alpha-hydroxy acids and keto acids have also been recognized as usefulfor treating a number of other skin conditions. For instance, U.S. Pat.No. 3,920,835 describes a treatment for skin lesions which accompanydisturbed keratinization. Examples of this condition include dandruff,acne, palmar and plantar (hand and foot) hyperkeratosis and palmar andplantar callouses which are secondary manifestations of eczema orchronic friction. For additional disclosures, please see U.S. Pat. Nos.3,984,566 and 3,988,470.

Acne (acne vulgaris) is a very common condition for which a variety ofprescription and over-the-counter remedies are available. Benzoylperoxide is a common over-the-counter remedy. But, the active ingredientis a strong oxidizing agent which may cause allergic or dermatiticreactions. U.S. Pat. No. 4,021,572 describes the use of lactamides andquaternary ammonium lactates for acne treatment. Lactic acid is auseful, but potentially irritating compound. Non-irritating compositionsare formed when lactic acid is first reacted with a suitable base, suchas ammonium hydroxide or an alkyl amine.

The condition of dry skin is characterized by cracking, flaking and/orscaling. U.S. Pat. No. 4,105,733 describes the treatment of thiscondition with free acids, or the amide and/or ammonium salts ofselected acids, including α-hydroxy and keto acids.

U.S. Pat. Nos. 4,363,815; 4,380,549 and 5,091,171 should also be notedfor their various disclosures of α-hydroxy and/or keto acids and variousderivatives for the treatment of multiple ailments. Exemplaryderivatives of these compounds include the peroxide, amide, lactone,anhydride, ester and polymeric forms, as well as various organic orinorganic salts. Known acids and/or their derivatives may be combinedwith amphoteric compounds (such as peptides and polypeptides) orpseudoamphoteric compounds (such as creatinine). In addition to the skinconditions already mentioned, these compositions are useful for treatingpsoriasis, pruritus, age spots, melasmas, wrinkles, warts, blemishes,hyperpigmentation, inflammatory dermatoses and the like.

Compositions which reduce dryness or flakiness and improve thesuppleness or smoothness of skin are also known in the art. Thesecompositions comprise effective amounts of an hydroxylated carboxylicacid having 4-12 carbon atoms, in combination with a cosmeticallyacceptable vehicle other than water--which is not excluded, but anothervehicle must be present.

Additional acne medications are available for use over-the-counter.These formulations typically contain sulfur, resorcinol, salicylic acidand benzoyl peroxide or combinations thereof. Recent products includeretinol (Vitamin A) and various derivatives, such as retinoic acid, alsoknown as tretinoin and Retin-A, have been used for the treatment ofsevere acne. See, for example, U.S. Pat. No. 3,006,939 which relates toretinoic acid; and U.S. Pat. No. 4,826,828 which describes thepreparation of stable retinol compositions, especially for reducingwrinkles.

U.S. Pat. Nos. 3,932,665 and 4,934,114 disclose the use of retinal(Vitamin A aldehyde) for the treatment of ache and skin keratoses,respectively. U.S. Pat. No. 3,060,229 also illustrates the state of thisart. Retinal and it derivatives have found application in the treatmentof wrinkles, warts, psoriasis, eczema, dandruff and like conditions(EP-A2-0 391 033). There are also suggestions that tretinoin can heal orreverse the effects of photoaging. Representative publications includeKligman, "Current Status of Topical Tretinoin in the Treatment ofPhotoaged Skin," Drugs & Aging, 2(1):7-13 (1992); Ellis, "Tretinoin: ItsUse in Repair of Photodamage," and Zelickson, "Topical Tretinoin inPhotoaging: An Ultrastructural Study," both presented in the Journal ofCutaneous Aging & Cosmetic Dermatology, Vol. 1, No. 1, pp. 33-40 and41-47 (1988).

Vitamin C (ascorbic acid) and its derivatives are other compounds whichhave been topically applied as the active ingredient for the treatmentof various skin conditions. U.S. Pat. No. 4,983,382 describes thepreparation of stabilized ascorbic acid compositions for topicalapplication. See also, U.S. Pat. Nos. 5,140,043 and 5,122,536 whichdescribe the use of ascorbic acid for preventing ultraviolet damage andtreating psoriasis.

With these and other known ingredients, end-users may suffer fromirritation or dermatitis due to the active ingredient, the vehicle or acombination of both. The source of these dermatoses is not always thesame, and the reason is not always apparent. For example, a skin rashmay result because the active ingredient or vehicle causes a drycondition similar to the action of soap. Irritation may also arise fromthe transdermal administration of an active ingredient. And, theconformational and/or stereochemistry of the active ingredient mayinduce an allergic-type irritation.

It will be appreciated that any irritation caused by treatment for agiven skin condition is undesirable. These conditions typically have anon-aesthetic appearance, which is often the reason a patient seekstreatment in the first instance. Poor aesthetic appearance of the skinmay be (or may appear to be) aggravated by treatment when irritation iscaused by the active ingredient. Adverse cosmetic reactions may worsenwith continuing use of a particular active ingredient over an extendedperiod of time. These negative results can be quite disturbing to thepatient. And, they may prompt a patient to discontinue treatment orneglect the original condition. The end-user or physician may reduce thenumber of treatments or lower the concentration of active ingredient(again reducing the effectiveness of treatment).

Therefore, it would be desirable to reduce or eliminate irritationresulting from the treatment of skin conditions, regardless of whetherthis condition is caused by the active ingredient, the vehicle or somecombination thereof.

It may also be desirable to topically apply higher concentrations ofactive ingredient for better efficacy or to enhance the effect of apre-selected active ingredient, thereby permitting less frequent or lessconcentrated administration of the active ingredient.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a topically applieddermatological agent which eliminates or reduces the occurrence ofirritation which may accompany treatment of a skin condition.

It is another object of the present invention to provide a topicallyapplied dermatological agent which includes higher concentrations ofactive ingredients used to treat a variety of skin conditions.

A further object of the present invention is to provide a topicallyapplied dermatological agent with improved efficacy.

Yet another object of the present invention is to provide a topicallyapplied dermatological agent which exhibits shorter response time forabsorption and clearance (dissipation) into several layers of skin.

It is still another object of the present invention to provide acosmetically or pharmaceutically acceptable vehicle which enhances theeffect of an active ingredient, thereby permitting lower concentrationsof active ingredient and reducing possible incidence of irritation.

In brief, then, the invention generally provides a dermatological agentwhich includes an active ingredient and a cosmetically orpharmaceutically acceptable vehicle. This dermatological agent comprisesan amount of ascorbic acid, or a derivative thereof, effective to reduceirritation caused by the composition topically administered to thepatient.

This invention also provides a separate topical vehicle which includesat least one inert composition and an amount of ascorbic acid, or itsderivatives, effective to reduce irritation caused by the activeingredient or vehicle, or a combination thereof.

Still further, this invention provides a method for reducing skinirritation which comprises the topical application of an activeingredient with an amount of ascorbic acid (or a derivative thereof)which is effective to reduce irritation caused by the active ingredientor other constituents. The ascorbic acid composition and activeingredient may be combined in a cosmetically or pharmaceuticallyacceptable vehicle, or the ascorbic acid composition and activeingredient may be topically applied in separate solutions.

DETAILED DESCRIPTION OF SPECIFIC EMBODIMENTS

As just summarized, this invention is generally directed todermatological agents which include an active ingredient used to treat askin condition and an amount of ascorbic acid, or a derivative thereof,effective for reducing irritation. While this specification is primarilydirected to illustrating the invention with respect to activeingredients which induce irritation, it should be appreciated thatirritation may be caused by the vehicle (without the ascorbic acid) orby a combination thereof.

The active ingredient may be any of those described in the admittedreferences which are incorporated by reference herein, or any otheractive ingredient which is administered in a topical formulation. Thepresence of ascorbic acid reduces the occurrence or severity ofirritation and/or provides for higher concentrations of activeingredient without causing irritation.

The present invention contemplates the use of compounds which release orconvert to ascorbic acid and/or its derivatives when topically appliedor administered to skin. Derivatives of ascorbic acid includepharmaceutically and dermatologically acceptable salts, esters, reverseesters and anhydrides. Examples include alkali salts such as sodiumascorbate (U.S. Pat. No. 2,442,005, incorporated by reference herein)and potassium ascorbate; alkaline earth salts such as calcium ascorbate(U.S. Pat. Nos. 2,596,103 and 2,442,461, incorporated by referenceherein); magnesium ascorbate and compatible mixtures. Exemplary estersinclude ascorbyl palmitate, ascorbyl laureate, ascorbyl myristate,ascorbyl stearate and compatible mixtures. Other salts, such asmagnesium ascorbyl phosphate, are also suitable.

In general, ascorbic acid and/or any derivative thereof will be presentin amounts of at least about 0.5%, more preferably at least about 5%,and most preferably at least about 10% based on the weight of thecomposition (all percentages are expressed on a weight basis unlessotherwise noted). The ascorbic acid or derivative compound is preferablypresent in effective amounts of not more than about 25%, more preferablyin amounts of not more than about 20%, and most preferably in amounts ofnot more than about 15%.

In addition to ascorbic acid and/or derivative(s), the dermatologicalagent includes at least one inert vehicle which should be essentiallyhypoallergenic. That is, the vehicle should not induce adverse effectson the skin or aggravate the condition being treated. The vehicle shouldnot deactivate the ascorbic acid, its derivatives or the activeingredient by chemical alteration of a constituent compound or byinterference with the absorption or action of a constituent compound.

Suitable inert vehicles can be identified from the literature or byroutine experimentation. They may be simple solutions (e.g., isotonicsaline), or emulsified mixtures including one or more componentsselected from water, organic solvents, oils, emulsifiers and the like.The vehicle should be chosen for its ability to solubilize or disperseboth the ascorbic acid (including derivatives as may be present) and theactive ingredient.

Exemplary vehicles include water (preferably distilled ordemineralized), alcohol (e.g., ethanol, isopropanol), propylene glycol,glycerin and mixtures thereof as the diluent. Ascorbic acid and itsderivatives, as well as many dermatologic agents, are solid at ambienttemperature and demonstrate varying degrees of solubility in water, oilsand organic solvents. For topical application, ascorbic acid and theactive ingredient are solubilized in the vehicle. If necessary, anemulsifier or surfactant may be used to facilitate solubilization ofascorbic acid or the active ingredient.

The dermatological agent may also include conventional adjuvants, suchas viscosity modifying agents, preservatives, humectants, demulcents,moisturizers, colorants, fragrances and compatible mixtures thereof.Exemplary viscosity modifying agents include hydroxylpropyl celluloseand carboxymethyl cellulose. Antioxidants or preservatives may includeany compositions which are readily available and well known in the art.

The formulation may also include a dispersant for one or more of thecomponents, such as a colorant or fragrance. Suitable dispersantsinclude various polyhydric alcohol anhydride partial higher fatty acidesters, e.g., Span 20, sorbitan monolaurate; Span 40, sorbitanmonopalmitate; Span 60, sorbitan monostearate; Span 65, sorbitantristearate; Span 80, sorbitan monooleate; Span 85, sorbitan trioleateor similar compounds, including Tween 20, sorbitan monolauratepolyoxyalkylene; Tween 40, sorbitan monopalmitate polyoxyalkylene; Tween65, polyoxyethylene sorbitan tristearate and the like.

The novel composition thus comprises at least one inert vehicle incombination with an effective amount of ascorbic acid and/orderivative(s) thereof, formulated for topical administration of adermatologically active ingredient.

The active ingredient may be any of those noted in this specificationincluding, without limitation, α-hydroxy acids, keto acids, Vitamin Aand derivatives thereof, salicylic acid, hydroquinone (for skinlightening) and compatible mixtures thereof. Suitable α-hydroxy acids,and related acids such as β-hydroxy acids, generally have two to sixcarbon atoms. Examples include glycolic acid, lactic acid, citric acid,malic acid, tartronic acid, tartaric acid, glycuronic acid, pyruvicacid, 2-hydroxyisobutyric acid, 3-hydroxybutyric acid, and derivativesthereof, such as esters and reverse esters with alcohols having one tosix carbon atoms (e.g., methyl pyruvate).

Other active ingredients include Vitamin A₂ (3,4-didehydroretinol),hepaxanthin (Vitamin A epoxide; 5,6-epoxy-5,6-dihydroretinol) andadditional derivative compounds. See, for example, the Food and DrugAdministration's Final Monograph for Topical Acne Products forOver-the-Counter Human Use, Federal Register, Vol. 56, No. 159 (1991).

Prior to illustrating the invention with specific examples, the assayfor testing degrees of irritation and/or dermatitis will be described.

Irritation Assay

The testing universe includes twenty (20) female subjects. A particularformulation is applied to a large area of skin twice daily for seven (7)consecutive days. Observations of the skin are recorded daily, as wellas at the end of the seven day period.

The types of irritation response include, alone or in combination,symptoms such as papules, pustules, tiny pinpoint bumps or largerindividual bumps. Diffuse erythema (unusual redness due to capillarycongestion) is normally present with a widespread follicular response,although it may be the sole expression of irritation. The followingcategories of irritation patterns were possible during testing of thenovel formulations of this invention.

Response Type 1

A few (e.g., 2-4 ) scattered papules-pustules over the treatment site,or a few (e.g., 1-3) bumps which persist for only a short duration, inwhich there is no subjective discomfort. The papules-pustules maydissipate with continued application of the formulation being tested; orthey may persist, without additional occurrences, until completion ofthe testing.

Response Type 2

Various forms of erythema with or without papular-pustular/bumpresponses such as (i) diffuse, minimal erythema throughout the treatmentsite, (ii) tiny, pinpoint flat erythematous dots or (iii) erythematouspatches. None of these responses are considered significant unless theyare persistent, associated with subjective discomfort or clearly moresevere than a Type 1 response.

Response Type 3

This type of response is characterized by numerous, tiny pinpoint bumpscovering the treatment site or larger individual bumps (about 10 toabout 30 of varied sizes), accompanied by several papules and/orpustules. Erythema may be specific to the bumps or may be diffusethroughout the entire region. This type of response is normallyaccompanied by severe itching which does not dissipate. The responseitself, as well as the subjective discomfort, intensifies with continueduse of the formulation. This type of response is characterized as asignificant reaction.

The present invention will now be described in connection with thefollowing examples.

EXAMPLE I

Glycolic acid is an α-hydroxy acid known to improve certain skindisorders such as dry skin, ichthyosis and acne. It is also useful forhealing photodamaged skin. High concentrations (e.g., 10%) of glycolicacid are effective for treating these disorders. But, glycolic acid cancause significant irritation at these concentrations. This irritation ischaracterized by bumps, papules, pustules and erythema, and/or astinging or similarly uncomfortable sensation. To evaluate the presentinvention, the following dermatological agents were prepared.

    __________________________________________________________________________    Ingredients  Composition A                                                                         Composition B                                                                          Function                                        __________________________________________________________________________    Demineralized Water                                                                        10.713   5.713   diluent                                         Alcohol      57.562  57.562   diluent                                         Hydroxypropyl Cellulose                                                                     0.500   0.500   thickener                                       Propylene Glycol                                                                           21.000  21.000   diluent                                         Butylated Hydroxytoluene                                                                    0.200   0.200   antioxidant                                     Color Solution                                                                              0.025   0.025   color                                           Glycolic Acid                                                                              10.000  10.000   active ingredient                               Ascorbic Acid                                                                              --       5.000   vehicle additive                                             100.000 100.000                                                  __________________________________________________________________________

The pH for Compositions A and B was approximately 2.4. Both compositionswere evaluated by the irritation assay described above. Each compositionwas applied twice daily to 20 subjects for seven days. Two of theComposition A subjects demonstrated Type 3 irritation responses. Inaddition, one subject reported discomfort. For the 20 subjects usingComposition B, no irritation responses were recorded and none of thesubjects experienced discomfort.

EXAMPLE II

The general procedure of Example I was repeated using glycolic acidpartially neutralized with ammonium hydroxide in the followingformulations.

    __________________________________________________________________________    Ingredient  C    D    E    F    Function                                      __________________________________________________________________________    Demin. Water                                                                              92.516                                                                             86.519                                                                             80.920                                                                             74.320                                                                             Diluent                                       Propylene Glycol                                                                          4.000                                                                              4.000                                                                              4.000                                                                              4.000                                                                              Diluent                                       Glycerin    2.000                                                                              2.000                                                                              2.000                                                                              2.000                                                                              Diluent                                       Hydroxyethyl Cellulose                                                                    1.200                                                                              1.200                                                                              1.200                                                                              1.200                                                                              Thickener                                     Fragrance   0.030                                                                              0.030                                                                              0.030                                                                              0.030                                              Tween 20 Dispersant                                                                       0.150                                                                              0.150                                                                              0.150                                                                              0.150                                              Citric Acid Modifier                                                                      0.005                                                                              --   --   --   pH                                            Amm. Hydrox.                                                                              --   2.101                                                                              2.700                                                                              4.300                                              Glycolic Acid                                                                             --   4.000                                                                              4.000                                                                              4.000                                              Ascorbic Acid                                                                             --   --   5.000                                                                              10.000                                                         100.000                                                                            100.000                                                                            100.000                                                                            100.000                                            __________________________________________________________________________

The pH for Composition C was 5.08; 3.9 for Composition D; 3.7 forComposition E and 3.8 for Composition F. Using the irritation assaydescribed above, the ability of ascorbic acid to inhibit glycolicacid-induced irritation was evaluated.

The placebo, Composition C, did not elicit any Type 3 irritationresponse or discomfort. This result demonstrated suitable inertness ofthe vehicle.

Of the ten (10) subjects using Composition D, four (4) demonstrated Type3 irritation response. Accordingly, the presence of 4% glycolic acid inthe inert vehicle induces significant irritation.

Of the twenty (20) subjects using Composition E, four (4) demonstrated aType 3 irritation response. These results confirm the unexpected abilityof 5% ascorbic acid to avoid the irritation caused by glycolic acid.

Of the twenty (20) subjects using Composition F, two (2) displayed aType 3 irritation response. These results demonstrate the unexpectedability of 10% ascorbic acid to further reduce the incidents ofirritation caused by the active dermatologic ingredient.

The results achieved with the present invention are summarized in Table1 which is set forth below.

    ______________________________________                                                    %        %          % of Subjects                                             Glycolic Ascorbic   Tested Showing                                Composition Acid     Acid       Type 3 Irritation                             ______________________________________                                        C           0.0      0.0         0.0                                          D           4.0      0.0        40.0                                          E           4.0      5.0        20.0                                          F           4.0      10.0       10.0                                          ______________________________________                                    

These results clearly show that ascorbic acid is unexpectedly useful inpreventing irritation caused by topically applied active ingredients.

As an alternative embodiment of the present invention, the ascorbic acidis applied separately (rather than as a part of the vehicle). Forexample, a solution of ascorbic acid may be sprayed onto the skin beforeand/or after topical application of the active ingredient.

Such a method for reducing irritation would be especially useful inconnection with preformulated compositions, such as over-the-counterproducts. The user of such a product may immediately experience anoccurrence of irritation, or irritation may become manifest afterrepeated use of the product. Rather than reformulating an existingover-the-counter product, a solution of ascorbic acid in a suitabledispenser (e.g., a pump spray bottle) can be applied before and/or afteruse of the over-the-counter product.

In another embodiment, a solution of ascorbic acid can be admixed with apre-formulated medication (for example, a prescription drug) just priorto topical administration of the combined solution.

The descriptions and examples presented in this specification are meantto illustrate the invention without limiting effect. Variousmodifications and alterations to the present invention may beappreciated based on a review of this disclosure. These changes andadditions are intended to be within the scope and spirit of thisinvention as defined by the following claims.

What is claimed is:
 1. A method for reducing irritation induced by thetopical application of a dermatological agent which comprises an activeingredient and a cosmetically or pharmaceutically acceptable vehicle,said method comprising admixing said active ingredient with ascorbicacid (or a derivative thereof) prior to said topical application in anamount effective for reducing irritation induced by said dermatologicalagent.
 2. The method as defined by claim 1, wherein the ascorbic acid(or derivative thereof) is present in an effective amount of at leastabout 0.5% by weight of the dermatological agent.
 3. The method asdefined by claim 2, wherein the ascorbic acid (or derivative thereof) ispresent in an effective amount of not more than about 25% by weight ofthe dermatological agent.
 4. The method as defined by claim 1, whereinthe ascorbic acid (or derivative thereof) is present in an effectiveamount of at least about 5% by weight of the dermatological agent. 5.The method as defined by claim 4, wherein the ascorbic acid (orderivative thereof) is present in an effective amount of not more thanabout 20% by weight of the dermatological agent.
 6. The method asdefined by claim 1, wherein the ascorbic acid (or derivative thereof) ispresent in an effective amount of at least about 10% by weight of thedermatological agent.
 7. The method as defined by claim 6, wherein theascorbic acid (or derivative thereof) is present in an effective amountof not more than about 15% by weight of the dermatological agent.
 8. Themethod as defined by claim 1, wherein said active ingredient is selectedfrom the group consisting of retinol, salicylic acid, benzoyl peroxide,α-hydroxy acids, keto acids, hydroquinone and derivatives or compatiblemixtures thereof.
 9. A method for reducing irritation induced by thetopical application of a dermatological agent which comprises an activeingredient and a cosmetically or pharmaceutically acceptable vehicle,said method comprising the topical application of ascorbic acid (or aderivative thereof) to an area of a patient's skin to be treated withsaid dermatological agent in an amount effective for reducing irritationinduced by said dermatological agent.
 10. The method as defined by claim9, further comprising the application of a solution including from about0.5% to about 25% by weight of said ascorbic acid (or its derivative).11. The method as defined by claim 10, wherein said solution comprisesfrom about 5% to about 20% by weight of said ascorbic acid (or itsderivative).
 12. The method as defined by claim 11, wherein saidsolution comprises from about 10% to about 15% by weight of saidascorbic acid (or its derivative).
 13. A method for reducing irritationinduced by the topical application of a dermatological agent whichcomprises an active ingredient and a cosmetically or pharmaceuticallyacceptable vehicle, said method comprising the topical application ofascorbic acid (or a derivative thereof) to an area of a patient's skinpreviously treated with said dermatological agent in an amount effectivefor reducing irritation induced by said dermatological agent.
 14. Themethod as defined by claim 13, further comprising the application of asolution including from about 0.5% to about 25% by weight of saidascorbic acid (or its derivative).
 15. The method as defined by claim14, wherein said solution comprises from about 5% to about 20% by weightof said ascorbic acid (or its derivative).
 16. The method as defined byclaim 15, wherein said solution comprises from about 10% to about 15% byweight of said ascorbic acid (or its derivative).